Angiogenesis is a physiologic process defined as the formation of new blood vessels from pre-existing vasculature. Overwhelming evidence illustrates that new vessel formation is the rate limiting step in tumor growth and metastasis. Inhibition of angiogenesis, therefore, could have far reaching implications in the treatment of head and neck cancer. Due to the complexity of this process, any global disruption in tumor angiogenesis would require innovative strategies that inhibit multiple steps along the angiogenesis pathway. Our preliminary studies reveal that copper suppression therapy utilizing a novel compound, Tetrathiomolybdate (TM), is one such promising approach. In multiple, in vivo and in vitro investigations utilizing breast, head and neck, and Lewis lung carcinoma, TM has dramatically inhibited angiogenesis, halted tumor growth, worked synergistically with cytotoxic therapy and prevented microscopic tumors from obtaining the blood supply needed to become clinically visible. TM's mechanism of action is achieved by sustained inhibition of NF-kappaB, a nuclear transcription factor with receptors found in the promoter regions of multiple pro-angiogenic cytokines. We hypothesize that NF-kappaB inhibition results in a marked inhibition of angiogenesis and an increased responsiveness to cytotoxic therapy. We will test our hypotheses in vito utilizing well characterized cell lines and in vivo with human tumor murine xenografts. The relationship of NF-kappaB expression with cytotoxic therapy responsiveness will be evaluated using the Veterans? Affairs Laryngeal Cooperative Study #268 tissue samples. Taken together, the information acquired in this work will be used to design a new clinical trial utilizing TM either as a chemopreventative agent for patients at high risk for recurrence or as an adjunct to improve the efficacy of existing chemo/radiation therapy regimen.